All animals, including humans, show differential susceptibility to infection with viruses. Study of the genetics of susceptibility or resistance to specific pathogens is most easily studied in mice. We have been using mouse mammary tumor virus (MMTV), a retrovirus that causes mammary tumors in mice, to study virus/host interactions. These studies have focused on understanding the mechanisms which determine genetic susceptibility to MMTV infection in vivo, using different inbred, transgenic and knockout mice. This approach has led to identification of many of the steps that MMTV uses in vivo to take advantage of its host, as well an understanding of the genetics of host resistance to virus infection. In the next funding period, we will continue to use genetic approaches to study genes that affect the interaction of MMTV with lymphocytes. In the first Aim, we will study the role of a family of receptors involved in innate immunity, the toll-like receptors (TLR), that we have recently shown are involved in an early step in the MMTV infection pathway, stimulation of B cells. In this aim, we use mice with naturally occurring or targeted mutations in the TLR2, TLR4, RP105 and myd88 genes to determine how signaling through TLR molecules is important for MMTV infection. In the second Aim, we will continue our functional studies on an as of yet unidentified locus in B10.BR mice that confers resistance to MMTV infection at a later step, probably at the level of virus spread in lymphocytes. We will determine what step in the infection pathway is affected in these mice. The results obtained from these studies will greatly increase our understanding of the genetic mechanisms which viruses use to infect their hosts and how genetic resistance to such viruses in the hosts occurs.